MX2007016393A - Combinacion de un inhibidor de renina y un potenciador de la secrecion de insulina o un sensibilizante a la insulina. - Google Patents

Info

Publication number

MX2007016393A

MX2007016393A MX2007016393A MX2007016393A MX2007016393A MX 2007016393 A MX2007016393 A MX 2007016393A MX 2007016393 A MX2007016393 A MX 2007016393A MX 2007016393 A MX2007016393 A MX 2007016393A MX 2007016393 A MX2007016393 A MX 2007016393A

Authority

MX

Mexico

Prior art keywords

amide

methyl

piperazin

carboxylic acid

benzoyl

Prior art date

2005-07-01

Links

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• Global Dossier
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• 230000003914 insulin secretion Effects 0.000 title claims abstract description 59
• 239000003623 enhancer Substances 0.000 title claims abstract description 58
• 239000002461 renin inhibitor Substances 0.000 title claims abstract description 57
• 229940086526 renin-inhibitors Drugs 0.000 title claims abstract description 56
• 229940122355 Insulin sensitizer Drugs 0.000 title claims abstract description 40
• 150000003839 salts Chemical class 0.000 claims abstract description 137
• 239000003814 drug Substances 0.000 claims abstract description 30
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
• 229940124597 therapeutic agent Drugs 0.000 claims abstract description 21
• 238000002360 preparation method Methods 0.000 claims abstract description 6
• 229910052739 hydrogen Inorganic materials 0.000 claims description 306
• 239000001257 hydrogen Substances 0.000 claims description 306
• WCGBJDMVMJWYNK-UHFFFAOYSA-N 6-[4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]pyridazine-3-carboxylic acid Chemical compound N1=NC(C(=O)O)=CC=C1N1CCN(C(=O)C=2C(=CC=CC=2)C(F)(F)F)CC1 WCGBJDMVMJWYNK-UHFFFAOYSA-N 0.000 claims description 301
• 125000004432 carbon atom Chemical group C* 0.000 claims description 274
• -1 3-methoxy-propyloxy Chemical group 0.000 claims description 218
• 125000000217 alkyl group Chemical group 0.000 claims description 209
• 150000002431 hydrogen Chemical group 0.000 claims description 186
• 125000003118 aryl group Chemical group 0.000 claims description 180
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 168
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 103
• 125000000623 heterocyclic group Chemical group 0.000 claims description 97
• 150000001875 compounds Chemical class 0.000 claims description 96
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 93
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 89
• 229910052736 halogen Inorganic materials 0.000 claims description 85
• 150000002367 halogens Chemical group 0.000 claims description 85
• 125000003545 alkoxy group Chemical group 0.000 claims description 84
• 229910052760 oxygen Inorganic materials 0.000 claims description 82
• 229910052757 nitrogen Inorganic materials 0.000 claims description 77
• ZOGZOXRETBBBJI-UHFFFAOYSA-N 2-cyclopropylethanamine Chemical compound NCCC1CC1 ZOGZOXRETBBBJI-UHFFFAOYSA-N 0.000 claims description 75
• 229910052717 sulfur Inorganic materials 0.000 claims description 72
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 70
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 69
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 69
• 229910052799 carbon Inorganic materials 0.000 claims description 65
• 150000003254 radicals Chemical group 0.000 claims description 65
• 239000004202 carbamide Substances 0.000 claims description 64
• 101100439664 Arabidopsis thaliana CHR8 gene Proteins 0.000 claims description 61
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 59
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 57
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 50
• 239000001301 oxygen Substances 0.000 claims description 50
• 206010020772 Hypertension Diseases 0.000 claims description 49
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 48
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 42
• 125000002252 acyl group Chemical group 0.000 claims description 41
• 206010012601 diabetes mellitus Diseases 0.000 claims description 41
• 239000008103 glucose Substances 0.000 claims description 41
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 40
• 230000001771 impaired effect Effects 0.000 claims description 40
• 239000011593 sulfur Chemical group 0.000 claims description 40
• 125000001072 heteroaryl group Chemical group 0.000 claims description 39
• 238000011282 treatment Methods 0.000 claims description 37
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 36
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 36
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 36
• 230000003287 optical effect Effects 0.000 claims description 35
• 230000000694 effects Effects 0.000 claims description 33
• 201000009104 prediabetes syndrome Diseases 0.000 claims description 33
• 125000004001 thioalkyl group Chemical group 0.000 claims description 33
• 125000004104 aryloxy group Chemical group 0.000 claims description 32
• 125000002947 alkylene group Chemical group 0.000 claims description 30
• 238000000034 method Methods 0.000 claims description 30
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 30
• 125000005000 thioaryl group Chemical group 0.000 claims description 28
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
• 230000002792 vascular Effects 0.000 claims description 27
• 208000002705 Glucose Intolerance Diseases 0.000 claims description 26
• 206010019280 Heart failures Diseases 0.000 claims description 26
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 26
• HNVMNKRBPNWQCQ-UHFFFAOYSA-N 6-[4-[5-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]pyridazine-3-carboxylic acid Chemical compound N1=NC(C(=O)O)=CC=C1N1CCN(C(=O)C=2C(=CC=C(F)C=2)C(F)(F)F)CC1 HNVMNKRBPNWQCQ-UHFFFAOYSA-N 0.000 claims description 25
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 25
• 102000004877 Insulin Human genes 0.000 claims description 24
• 108090001061 Insulin Proteins 0.000 claims description 24
• 239000002253 acid Substances 0.000 claims description 24
• 229940125396 insulin Drugs 0.000 claims description 24
• 125000005415 substituted alkoxy group Chemical group 0.000 claims description 24
• 125000004442 acylamino group Chemical group 0.000 claims description 23
• BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 claims description 23
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
• 102000030595 Glucokinase Human genes 0.000 claims description 21
• 108010021582 Glucokinase Proteins 0.000 claims description 21
• 201000010099 disease Diseases 0.000 claims description 21
• 230000001631 hypertensive effect Effects 0.000 claims description 21
• 125000003282 alkyl amino group Chemical group 0.000 claims description 20
• 239000003112 inhibitor Substances 0.000 claims description 20
• GIUNXTSWTSQHTH-UHFFFAOYSA-N [6-[4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]pyridazin-3-yl]urea Chemical compound N1=NC(NC(=O)N)=CC=C1N1CCN(C(=O)C=2C(=CC=CC=2)C(F)(F)F)CC1 GIUNXTSWTSQHTH-UHFFFAOYSA-N 0.000 claims description 19
• 239000000651 prodrug Substances 0.000 claims description 19
• 229940002612 prodrug Drugs 0.000 claims description 19
• 206010022489 Insulin Resistance Diseases 0.000 claims description 18
• 108090000783 Renin Proteins 0.000 claims description 18
• 125000001769 aryl amino group Chemical group 0.000 claims description 18
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 18
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 18
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 18
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 18
• 125000005842 heteroatom Chemical group 0.000 claims description 18
• 230000005764 inhibitory process Effects 0.000 claims description 18
• 102100028255 Renin Human genes 0.000 claims description 17
• 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 17
• 101710159293 Acyl-CoA desaturase 1 Proteins 0.000 claims description 16
• 230000002265 prevention Effects 0.000 claims description 16
• 230000004153 glucose metabolism Effects 0.000 claims description 15
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
• 206010007559 Cardiac failure congestive Diseases 0.000 claims description 14
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 14
• 206010055171 Hypertensive nephropathy Diseases 0.000 claims description 14
• 208000002780 macular degeneration Diseases 0.000 claims description 14
• 208000010159 IgA glomerulonephritis Diseases 0.000 claims description 13
• 206010021263 IgA nephropathy Diseases 0.000 claims description 13
• RTMFZNZPHCZAFG-UHFFFAOYSA-N 6-[[3-(2-methylpropoxy)-5-propan-2-yloxybenzoyl]amino]pyridine-3-carboxylic acid Chemical group CC(C)COC1=CC(OC(C)C)=CC(C(=O)NC=2N=CC(=CC=2)C(O)=O)=C1 RTMFZNZPHCZAFG-UHFFFAOYSA-N 0.000 claims description 12
• 206010048554 Endothelial dysfunction Diseases 0.000 claims description 12
• 230000008694 endothelial dysfunction Effects 0.000 claims description 12
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
• 208000001145 Metabolic Syndrome Diseases 0.000 claims description 11
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 11
• 229940124828 glucokinase activator Drugs 0.000 claims description 11
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
• SNQBJBVXPVCDLA-UHFFFAOYSA-N 5-[[3-propan-2-yloxy-5-(2-thiophen-3-ylethoxy)benzoyl]amino]-1,3,4-thiadiazole-2-carboxylic acid Chemical compound C=1C(C(=O)NC=2SC(=NN=2)C(O)=O)=CC(OC(C)C)=CC=1OCCC=1C=CSC=1 SNQBJBVXPVCDLA-UHFFFAOYSA-N 0.000 claims description 10
• 201000001320 Atherosclerosis Diseases 0.000 claims description 10
• 241001465754 Metazoa Species 0.000 claims description 10
• 125000003342 alkenyl group Chemical group 0.000 claims description 10
• 125000000304 alkynyl group Chemical group 0.000 claims description 10
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 10
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• 208000010125 myocardial infarction Diseases 0.000 claims description 10
• YNOOQIUSYGWMSS-UHFFFAOYSA-N 2,5-difluoroaniline Chemical compound NC1=CC(F)=CC=C1F YNOOQIUSYGWMSS-UHFFFAOYSA-N 0.000 claims description 9
• MGAPESYORZVKQD-UHFFFAOYSA-N 2-cyclobutylethanamine Chemical compound NCCC1CCC1 MGAPESYORZVKQD-UHFFFAOYSA-N 0.000 claims description 9
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• 230000001965 increasing effect Effects 0.000 claims description 9
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
• 108020000494 protein-tyrosine phosphatase Proteins 0.000 claims description 9
• XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 claims description 9
• 239000005711 Benzoic acid Substances 0.000 claims description 8
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• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
• ZSPRIOXATHSHPO-UHFFFAOYSA-N n-(4-methylpentyl)-6-[4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]pyridazine-3-carboxamide Chemical compound N1=NC(C(=O)NCCCC(C)C)=CC=C1N1CCN(C(=O)C=2C(=CC=CC=2)C(F)(F)F)CC1 ZSPRIOXATHSHPO-UHFFFAOYSA-N 0.000 claims description 8
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• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 7
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